I. The Indolocarbazole K-252a
K-252a is a compound having an indolocarbazole skeleton [Japanese Published Unexamined Patent Application No. 41489/85 (U.S. Pat. No. 4,555,402)] with the stereochemistry shown in Formula I. ##STR2##
It has been reported that K-252a strongly inhibits protein kinase C (PKC) which plays a central role in regulating cell functions, and has various activities such as the action of inhibiting smooth muscle contraction (Jpn. J. Pharmacol. 43 (suppl.): 284, 1987), the action of inhibiting elongation of neurazone (J. Neuroscience, 8: 715, 1988), the action of inhibiting histamine release (Allergy, 43: 100, 1988), the action of inhibiting smooth muscle MLCK (J. Biol. Chem., 263: 6215, 1988), anti-inflammatory action (Acta Physiol. Hung., 80: 423, 1992), and the activity of cell survival (J. Neurochemistry, 64: 1502, 1995). It has also been disclosed in Experimental Cell Research, 193: 175-182, 1991, that K-252a has the activity of inhibiting IL-2 production.
In addition, it has been reported that derivatives of K-252a have PCK inhibitory activity, the activity of inhibiting histamine release (Japanese Published Unexamined Patent Application No. 295588/88), antitumor activity [Japanese Published Unexamined Patent Application No. 168689/89 (U.S. Pat. No. 4,877,776), WO 88/07045 (U.S. Pat. No. 4,923,986), WO 94/04541], the action of increasing blood platelets [WO 94/06799 (EP 630898A)], vasodepressor activity (Japanese Published Unexamined Patent Application No. 120388/87), the action of accelerating cholinergic neuron functions [WO 94/02488 (U.S. Pat. No. 5,461,146 and U.S. Pat. No. 5,621,100)] and, curative effect on prostate cancer [WO 94/27982 (U.S. Pat. No. 5,516,771)]. Selected amino-containing trindene compounds have been prepared by Beckmann rearrangement of the corresponding staurosporine oximes (WO 97/05140).
The indolocarbazoles are generally lypophilic. Because of this feature, the indolocarbazoles are able to cress biological membranes with relative ease, compared to proteins. Also indolocarbazoles generally have longer in vivo half lives than proteins.
In addition to K-252a itself, various derivatives of K-252a have been synthesized and tested for biological activity. Among the K-252a derivatives shown to have biological activity is a compound disclosed in Lewis et al., U.S. Pat. Nos. 5,461,146, and 5,621,100, and PCT Publication WO 94/02488, and designated therein as "Compound II-51." Compound II-51 has been shown to enhance the function of cholinergic neurons, striatal neurons, and sensory neurons.
II. Neurodegenerative Diseases and Disorders
Parkinson's disease is a neurodegenerative disorder that involves progressive and selective loss of dopaminergic neurons of the nigro-striatal pathway (Agid, Lancet: 337:1991). Administration of 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) to mice leads to dopaminergic neuron degeneration and serves as an animal model for the dopaminergic neuronal loss and behavioral deficits observed in Parkinson's disease. Peripheral administration of MPTP leads to a highly selective degeneration of the nigrostriatal dopaminergic neuronal system in humans, monkeys and mice (Heikkila et al., Science 224; 1451-1453, 1984; Burns et al., Proc Natl. Acad. Sci. USA 80:4546-4550, 1983).
Neurodegeneration in the MPTP mouse model has been well-characterized. Systemic administration of MPTP produces selective loss of dopamine content (and metabolites), tyrosine hydroxylase activity, and dopamine uptake sites in dopaminergic neurons of the murine striatum (Heikkila et al., Nature 311:467-469, 1984a,b; Tipton et al., J. Neurochem. 61:1191-1206, 1993). This effect is dose-dependent. Maximal loss occurs between 3 and 7 days post-lesion (Jackson-Lewis et al., Neurodegeneration 4:257-269, 1995). The dopaminergic cell bodies in the nigra are less sensitive to MPTP toxicity than their corresponding nerve terminals. At high MPTP doses, or multiple MPTP injections, substantial loss of TH immunopositive cells in the substantia nigra occurs within a week (Heikkila et al., Science 224; 1451-1453, 1984; Jackson-Lewis et al., Neurodegeneration 4:257-269, 1995). At lower MPTP doses, or with a single injection, loss of nigral tyrosine hydroxylase positive cells occurs later (Tatton et al., J. Neuroscience. Res. 30:666-672, 1991). Thus, at lower doses of MPTP and a short-time period after lesion, striatal damage can be observed in the absence of nigral tyrosine hydroxylase-positive cell loss. This neurodegenerative sequence is similar to that observed in the disease. The MPTP mouse model is a recognized and widely used model for the study of Parkinson's disease.
Non-cholinergic neurons that use .gamma.-aminobutyric acid (GABA) as a neurotransmitter (i.e., GABA-ergic neurons) are widespread throughout the brain. For example, they are found in the nucleus basalis magnocellularis in the rodent (the equivalent region in the human brain is called nucleus basalis of Meynert), a region of the basal forebrain important in attention and memory functions. Damage to GABA-ergic neurons in the basal forebrain may also contribute to behavioral deficits in neurodegenerative diseases such as Alzheimer's disease (Dekker et al., Neurosci. and Biobehav. Rev., 15:299-317, 1991; Gallagher et al., Seminars in Neuroscience, 6;351-358, 1994; Torres et al., Neuroscience, 63:95-122, 1994).
Neurons in the basal forebrain die in several diseases of the central nervous system, notably Alzheimer's disease (Arendt et al., Acta Neuropathol. (Berl.) 61:101-108, 1983; Iraizoz et al., Neuroscience, 41:33-40, 1991; Vogels et al., Neurobiol. Aging, 11:3-13, 1990). A contributing factor in such neuronal cell death is glutamate excitotoxity, i.e. over-stimulation of neurons by excess glutamate (Choi, Neuron, 1:623-634, 1988). Accordingly, several animal models of Alzheimer's disease use glutamate or a glutamate analog to produce excitotoxic death in the region of the basal forebrain where neuron death occurs, i.e., the nucleus basalis magnocellularis (Wenk, Beh. Brain Res., 72:17-24, 1996).
Neuronal pathology in Alzheimer's disease is first seen in the entorhinal cortex, and loss of neurons in this region becomes severe as the disease progresses (Braak et al., Acta Neuropathol. 82:239-259, 1991; Hyman et al., Ann. Neurol. 20:472-481, 1986). Neurons in layer 2 of the entorhinal cortex project to the dentate syrus of the hippocampus, and this neuronal pathway plays an important role in memory formation (Levisohn et al., Brain Res. 564:230-244, 1991; Olton et al., Brain Res. 139:295-308, 1978; Steward et al., Brain Res. Bull. 2:41-48, 1977). Neurons in layer 2 of the entorhinal cortex, like many other neurons in the cerebral cortex, use glutamate as a neurotransmitter (Mattson et al., Neuron 1:865-876, 1988; White et al., Nature 270:356-357, 1977). Thus, loss of flutamatergic neurons in the entorhinal cortex contributes to the behavioural deficits seen in Alzheimer's disease and other neurological disorders.
III. Peripheral Neuropathy
Peripheral neuropathy generally refers to a disorder that affects the peripheral nerves, most often manifested as one or a combination of motor, sensory, sensorimotor, or autonomic neural dysfunction. The wide variety of morphologies exhibited by peripheral neuropathies can each be uniquely attributed to an equally wide variety of causes. For instance, peripheral neuropathies can be genetically acquired, can result from a systemic disease, or can be induced by a toxic agent. Some toxic agents that cause neurotoxicities are therapeutic drugs, antineoplastic agents, contaminants in foods or medicinals, and environmental and industrial pollutants.
In particular, chemotherapeutic agents known to cause sensory and/or motor neuropathies include vineristine, an antineoplastic drug used to treat haematological malignancies and sarcomas. The neurotoxicity is dose-related, and exhibits as reduced intestinal motility and peripheral neuropathy, expecially in the distal muscles of the hands and feet, postural hypotension, and atony of the urinary bladder. Similar problems have been documented with taxol and cisplatin (Mollman, 1990, New Eng. Jour. Med. 322:126-127), although cisplatin-related neurotoxicity can be alleviated with nerve growth factor (NGF) (Apfel, et al., 1992, Annals of Neurology 31:76-80). Although the neurotoxicity is sometimes reversible after removal of the neurotoxic agent, recovery can be a very slow process (Legha, 1986, Medical Toxicology 1:421-427; Olesen, et al., 1991, Drug Safety 6:302-314).
There are a number of inherited peripheral neuropathies, including: Rofsum's disease, A-betalipoproteinemia, Tangier disease, Krabbe's disease, Metachromatic leukodystrophy, Fabry's disease, Dejerine-Sottas syndrome, and others. Of all the inherited neuropathies, the most common by far is Charcot-Marie-Tooth disease (see also, U.S. Pat. No. 5,420,112 for additional information on peripheral neuropathies).
IV. Cytokines
Tumor necrosis factor .alpha. (TNF-.alpha.) and interleukin-1.beta. (IL-1.beta.) are polypeptides known to be involved in a number of inflammatory and metabolic processes in vivo. For a review which relates the role of TNF-.alpha. in inflammatory diseases, including septic shock, see Ann. Rev. Immunol. 7:625 (1980), and Clinical Trials for the Treatment of Sepsis, Sibbald, W. J. and Vincent, J.-L. (Eds.), Springer-Verlag Berlin Heidelberg 1995. It is generally accepted that the overproduction or inappropriate production of TNF-.alpha. is involved in several pathological conditions, including septic shock (Spooner et al., Clinical Immunology and Immunopathology, 62:p. S11 (1992)) and various other allergic and inflammatory conditions or diseases, including but not limited to rheumatoid arthritis, osteoarthritis, asthma, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis, and inflammatory bowel disease, and other autoimmune diseases. Immunol. Res. 10:122 (1991), Science 229:896 (1985) and Proc. Natl. Acad. Sci. 89:7375 (1992).